Transdermal therapeutic system (TTS) with fentanyl as a active ingredient

ABSTRACT

The invention relates to a transdermal therapeutic systems with fentanyl or an analogous fentanyl derivative as active ingredient. In order to prevent inadvertent overdosage by uncontrolled release of active ingredient as a result of damage, the active ingredient is contained in fluid-filled micro-reservoirs in the layer containing the active ingredient. The layer containing the active ingredient can optionally be provided with a membrane.

FIELD OF THE INVENTION

The present invention relates to a transdermal therapeutic system (TTS)containing the active substance fentanyl.

BACKGROUND OF THE INVENTION

Fentanyl and fentanyl analog derivatives such as sulfentanyl,carfentanyl, lofentanyl, and alfentanyl are extremely active analgesics.Their low dosage and their physicochemical properties such as, forexample, the n-octanol/water partition coefficient, the melting point,and the molecular weight make it possible to supply the substancestransdermally in an effective amount, and their pharmacokineticproperties such as the rapid metabolization and the relatively narrowtherapeutic index make their transdermal supply desirable.

Indeed, for a number of years a fentanyl TTS has been on the market.This system is of the type known as a reservoir system. A reservoirsystem is a TTS which contains the active substance in a liquid or gelformulation in a pouch formed from an impermeable film and a membranewhich is permeable for the active substance. The impermeable film actsas a backing layer, in order to prevent the liquid or gel formulation ofthe active substance emerging on the side of the pouch facing away fromthe skin. The membrane serves to regulate the rate of active substancerelease from the skin-facing side of the pouch. On this side, themembrane additionally possesses an adhesive layer for attaching theoverall TTS to the skin.

In this specific case (Durogesic® TTS), fentanyl is in solution in amixture of ethanol and water. Further details of this system can befound in U.S. Pat. No. 4,588,580 or DE 35 26 339, both of which containa detailed description.

However, reservoir systems have a major disadvantage, namely that in theevent of a leak (e.g., a simple mechanically induced damage, a cut ortear, splitting of the weld seam, etc.) in the pouch containing theactive substance formulation, the active substance may come into contactwith the skin over a large area and, as a consequence of this contact,may be absorbed in, excessive doses. Especially in the case of fentanyland the fentanyl analog derivatives, this is potentially fatal, sinceoverdose leads very rapidly to respiratory depression and hence fatalincidents. A number of such fatal or near-fatal incidents have beendescribed in Clinical Pharmacokint.. 2000, 38 (1), 59-89.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a transdermaltherapeutic system comprising the active substance fentanyl and/orfentanyl analog derivatives which offers the user increased securityagainst inadvertent overdose.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the microreservoir system.

FIG. 2 illustrates the microreservoir system with membrane.

FIG. 3 illustrates the permeation profile of the microreservoir systemof FIG. 1.

FIG. 4 illustrates the permeation profile of the microreservoir systemof FIG. 2.

DETAILED DESCRIPTION OF THE INVENTION

This object is achieved by means of a transdermal therapeutic systemwhich comprises a backing layer, an active substance layer, and aprotective layer, to be removed before use. The active substance layeris composed of a polymer into which a multiplicity of liquidmicroreservoirs have been incorporated. These microreservoirs containthe active substance.

As has been found, despite the fact that the active substance iscontained in a liquid formulation within the active substance layer,said layer is absolutely leakproof even when damaged mechanically (cuts,tears, abrasion, etc.). The user is therefore at no risk in respect ofuncontrolled release or inadvertent overdose as a consequence ofunintended or deliberate damage to the active substance layer.

From a purely external standpoint, there is no difference between thiskind of transdermnal therapeutic system and the second major TTS type, amatrix system. With the TTS of the invention, the internal structure ofthe active substance layer can be perceived only under the microscope.The liquid microreservoirs are embedded in the form of small droplets inthe (preferably self-adhesive) active substance layer. (These dropletsadopt an approximately spherical form.) A transdermal therapeutic systemwith an active substance layer constructed in this way will be referredto hereinbelow as a “microreservoir system”.

These liquid microreservoirs have an average diameter of about 5-50 μm.In any case, however, they must be smaller than the thickness of theactive substance layer, since otherwise the active substance liquidcould escape. The size of the microreservoirs can be influenced by thechoice of suitable liquids and by regulating certain parameters duringthe preparation process.

Like a matrix system, the microreservoir system of the invention is thuscomposed at its most simple of three layers: a backing layer,impermeable to the active substance; the self-adhesive active substancelayer, with the microreservoirs; and a protective layer, to be removedbefore use. A system of this kind is illustrated in FIG. 1.

Even in the case of a microreservoir system, however, it may benecessary in certain circumstances to limit the amount of activesubstance to be delivered by the transdermal therapeutic system over acertain period of time. This can be achieved by means of a membranewhich adjoins the active substance layer on the skin side, and which forattachment to the skin may additionally be provided with an adhesivelayer. During the preparation process, this skin-side adhesive layer maybe provided with a limited amount of active substance which, followingapplication of such a microreservoir system, is delivered to the skinand hence into the organism in a way which cannot be controlled by themembrane. The purpose of this measure is to shorten the time until atherapeutic plasma level is reached (known as the “lag time”). Amicroreservoir system with membrane is depicted in FIG. 2.

Suitable active substances include fentanyl and/or fentanyl analogderivatives, preferably sulfentanyl, carfentanyl, lofentanyl, andalfentanyl. The active substance is preferably in the form of the freebase; altematively, it may be used in the form of a pharmaceuticallyacceptable salt or as a mixture of the free base with a pharmaceuticallyacceptable salt of said base. Examples of suitable salts include thehydrochlorides, hydrobromides, sulfates, hydrogen sulfates, citrates,and tartrates.

As already mentioned, fentanyl and the fentanyl analog derivativespossess a narrow therapeutic index. This means that the active substancerelease rate of a transdermal therapeutic system containing fentanyl ora fentanyl analog must be controlled with very great precision.

It has been found that the polymer or polymer blend which provides theactive substance layer with its internal cohesion, and in which themicroreservoirs are embedded, must meet certain requirements regardingdissolution capacity for the active substance and miscibility with theliquids which form the microreservoirs. Accordingly, the dissolutioncapacity for the active substance should be low, so that the majority ofthe active substance is located within the microreservoirs and not inthe polymer itself. Further, the polymer should be substantiallyimmiscible with the liquids which form the microreservoirs. Thesemeasures ensure that, first, the formation of microreservoirs isactually possible and that, secondly, the dissolution capacity of thepolymer phase for the active substance is not too high.

Polymers which have been found to be suitable include hydrophobicpolymers, which preferably possess pressure sensitive adhesion. Theseinclude polyisobutylenes and silicones (polysiloxanes). Amine-resistantpolysiloxanes have proven particularly suitable. In solubility studiesit has been found that the solubility of the active substance in suchpolymers is low. For example, fentanyl in base form has a solubility insuch polymers of less than 0.5% by weight.

Amine-resistant polymers of this kind are produced, for example, by DowCorning and are sold under the trade name BIO-PSA. The tackiness ofthese polymers ranges from nontacky via moderately strongly to stronglytacky, the appropriate tack also being adjustable by blending of theindividual types and/or by adding low molecular mass substances such assilicone oil, for example.

The advantage of the amine-resistant polysiloxanes is that they possessno free siloxanol groups and therefore do not tend to undergocondensation reactions in the presence of basic active substances orsalts of basic active substances, with adverse consequences for the bondstrength. Moreover, the interaction with the polar groups of the activesubstance molecules is lessened.

Solvents which can be used for the polymer include low-polarity and/orhydrophobic solvents. Amine-resistant polysiloxanes are offered in avariety of solvent systems. The most suitable solvents for theproduction of transdermal therapeutic systems in the context of thisinvention are n-heptane and comparable hydrocarbons, since the liquidsenvisaged for the microreservoirs are of only poor miscibility with thissolvent.

As a result, during preparation, the solution of the active substance inthe micro-reservoir liquid can be dispersed in the solution of thepolysiloxane and thus the size of the microreservoirs in the compositionto be coated can be set at this stage by virtue of the stirringconditions. For the purposes of the present description, a dispersion isa system which is composed of a continuous phase (which is made ofpolymer) and of the microreservoirs, which are not mutually contiguous(and which are made up of the liquid droplets).

The liquid, which constitutes an important ingredient of themicroreservoirs, should be at least partly miscible both with water andwith organic solvents. It may therefore also be referred to asambiphilic.

Moreover, the liquid should possess a good solvency for the activesubstance, in order to accommodate the required amount of activesubstance in customary TTS active substance layer thicknesses of about30 to 300 μm, correspond to a coating weight of 30-300 g/m².

Dipropylene glycol, diethylene glycol monoethyl ether, diethylene glycoldiethyl ether, diethylene glycol monomethyl ether, diethylene glycoldimethyl ether, 1,3-butanediol,2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane, 2-pyrrolidone, andN-methylpyrrolidone have proven particularly suitable. Instead of thesubstances alone it is of course also possible to take blends thereof.

The saturation solubilities of fentanyl, measured in different liquidssuitable for use as the microreservoirs, are shown in table 1.

TABLE 1 Saturation solubility of fentanyl in different liquidsMicroreservoir liquid Solubility [% w/w] 1,3-Butanediol 10 Dipropyleneglycol 18 Transcutol* 25 Diethylene glycol diethyl ether 26N-Methylpyrrolidone 26 *Diethylene glycol monoethyl ether

Accordingly, the solubility of fentanyl in base form is higher by afactor of about is 20-50 in the liquids envisaged for themicroreservoirs than in the polysiloxane polymer. This is more thansufficient to accommodate the required amount of active substance withina microreservoir matrix not exceeding 200 μm in thickness, in a systemwith an acceptable areal size.

The high solubility of fentanyl in the liquids envisaged for themicroreservoirs coupled with its low solubility in the silicone polymerhas the effect, moreover, that by far the predominant portion of thefentanyl is actually located within the microreservoirs and not insolution in the polymer phase.

Prior to application of a TTS of the invention, preferably more than 50%of the total active substance present in the TTS is situated within themicroreservoirs, since otherwise, because of the poor solubility in thepolymer, the active substance layers are too thick and the serviceproperties poor for the finished system.

The total concentration of the active substance in the active substancelayer is only between 2 and 5% by weight, which then also correspondsapproximately to the saturation concentration of the active substance inthe polymer. This means that, despite the low concentration, thethermodynamic activity of the active substance is at a maximum, i.e., ator just below 1.

The fraction of the microreservoirs in the active substance layer mayamount to up to 40% by weight, although it is advantageous not to exceed30% by weight.

It has proven advantageous to add to these liquids a substance whichraises their viscosity. Such substances may comprise polymers which arecapable of forming a gel with the liquid. Mention may be made by way ofexample of ethylcellulose and hydroxypropylcellulose, which are alsoused in the examples. This measure facilitates the dispersibility of theliquid in the solution of the polymer and may also result in smallermicroreservoir diameters.

For microreservoir systems of the invention which are provided with amembrane, either microporous membranes or what are known as distributionmembranes may be used. Microporous membranes are films provided withmicroscopic pores or channels. Here, the transport of active substanceis substantially through these pores or channels, which must thereforebe filled with a medium which is diffusible for the active substance(e.g., a liquid, gas, gel or other material). The number, the internalsurface area, and the size of the pores, and the physicochemicalproperties of the pore or channel filling substantially determine therelease of active substance (permeation rate).

Distribution membranes do not possess any pores; in other words, theactive substance must diffuse through the membrane material itself. Whenmembranes of this kind are used, it is the thickness of the membrane,and the solubility and diffusion coefficient of the active substance inthe membrane material, which determine the release of active substance.Distribution membranes which have proven particularly highly suitableare those based on copolymers of ethylene and vinyl acetate (EVA).Membranes of this kind are available in a variety of thicknesses andwith different compositions. Customary thicknesses range between 20 and150 μm, and the vinyl acetate (VA) content between 2 and 25% by weight.

Since the VA content has an effect on the solubility and the diffusioncoefficient of the active substances in the EVA polymers, it is afurther important membrane characterization parameter where membranesmade of this material are being used. In the examples, a membrane 50 μmthick with a VA content of 9% by weight has been used. The permeationrates achieved using this membrane can be raised through the use ofthinner membranes or membranes having a higher VA content. Naturally,the use of thicker membranes and the reduction of the VA content has theopposite effect.

Especially when systems without membrane control are used, the activesubstance intake, i.e., the amount of active substance delivered by theTTS that is actually absorbed via the skin into the blood circulation isalso dependent on the permeability of the skin. The outer skin layer inparticular, the stratum corneum, forms the principal barrier againstpenetrative active substances. This barrier function can be loweredthrough the use of what are called enhancers, thereby increasing theactive substance intake. Enhancers are known to the skilled worker, forexample, from the publication “Skin penetration enhancers cited in thetechnical literature” by David W. Osborne and Jill J. Henke, ViroTexCorporation, which can be called up on the Internet athttp://www.pharmtech.com/technical/osborne/osborne.htm and which inorder to avoid repetition is intended in its entirety to form part ofthe disclosure content of this specification.

For the transdermal therapeutic systems of the present invention it ispossible with particular advantage to use fatty acid, fatty acid ester,fatty alcohol or glycerol ester enhancers, especially when fentanyl isthe active substance being used.

For the preparation of the active substance layer, the active substanceis dissolved in the liquid which forms the microreservoirs, and thissolution is dispersed in the solution of the polymer. The resultingdispersion is then used to coat an appropriate substrate—normally apolyester film with an abhesive coating—the solvent of the polymer isremoved by drying. The drying conditions should be chosen such that onlya small proportion if any of the microreservoir solvent is removed. Ithas been found that the liquid and the solvent are preferably selectedsuch that the solvent possesses a boiling temperature which is at leastabout 30°, with particular preference at least 50°, below the boilingtemperature of the liquid.

The dry matrix film is then laminated to the backing layer of thesystem—usually an active substance impermeable film with a thickness ofabout 15 -30 μm—and the individual transdermal therapeutic systems arethen punched from the overall laminate obtained.

The production of corresponding microreservoir systems comprisingmembranes is somewhat more complicated, but in terms of the coating andlaminating process is no different from the production of known systemswith the same layer sequence. In the examples, the production ofmicroreservoir systems with and without membranes is described indetail.

Using three transdermal therapeutic systems provided by this invention,i.e. microreservoir systems with and without membranes, permeationstudies were conducted using human epidermis and Franz diffusion cells,which are known to the skilled worker. The composition and the resultsare summarized in tables 2 to 5, with the preparation process describedin detail in the examples.

TABLE 2 Composition of the microreservoir systems without membranesComposition [% w/w] Formulation A B C Ingredients Fentanyl base 2.0 3.65.0 BIO-PSA 4301* 80.0 80.0 80 1,3-Butanediol 17.46 Dipropylene glycol16.07 Transcutol** 14.4 Hydroxypropyl-cellulose 0.54 0.33 Ethylcellulose100 NF 0.6 Coating weight [g/m²] 130 85 65 Matrix thickness, 140 95 75approx. [μm] *Amine-resistant silicone adhesive with high bond strength**Diethylene glycol monoethyl ether

TABLE 3 Results of the permeation study with formulations A, B and CAverage Cumulative permeated release fentanyl base [μg/cm²]* rateFormulation 4 h 8 h 24 h 48 h 72 h (μg/cm² * h) A 1.2 9.5 84.4 194.0275.0 3.82 B 1.12 8.87 75.80 191.00 283.00 3.93 C 16.20 45.20 131.00212.00 262.00 3.64 *Averages of n = 3

TABLE 4 Composition of the systems with control membrane Composition [%w/w] Formulation D E F Ingredients Reservoir layer Fentanyl base 2.0 3.65.0 BIO-PSA 4301* 80.0 80.0 80 1,3-Butanediol 17.46 Dipropylene glycol16.07 Transcutol** 14.4 Hydroxypropyl-cellulose 0.54 0.33 Ethylcellulose100NF 0.6 Coating weight [g/m²] 130 85 65 Control membrane EVA membrane50 μm, 9% VA Skin contact layer BIO-PSA 4301* 100 100 100 Coating weight[g/m²] 35 35 35 *Amine-resistant silicone adhesive with high bondstrength **Diethylene glycol monoethyl ether

TABLE 5 Results of the permeation study with formulations D, E and FAverage Cumulative permeated release fentanyl base [μg/cm²]* rateFormulation 4 h 8 h 24 h 48 h 72 h [μg/cm² * h] D 1.4 4.9 26.2 64.0 99.81.39 E 2.7 8.1 37.0 85.0 129.0 1.79 F 0.8 4.7 45.3 114.0 166.0 2.31*Averages of n = 3

Comparing the permeation results of the microreservoir systems with andwithout a membrane it can be seen that the amount of active substancepermeated after 72 hours is much lower in the case of the membranesystems, despite the active substance layers having the samecomposition. This can be attributed to the controlling effect of themembrane, which limits the delivery of active substance to a maximumirrespective of the particular nature of the skin.

The graphs (FIGS. 3 and 4) also reveal that, as the result of the use ofa membrane, the permeation profile is more linear and hence also theactive substance intake in vivo is more uniform over the period of use.It is particularly evident in the case of formulation C, which shows thehighest permeation rate.

The TTS present on the market (Durogesic®) is available in 4 strengthswith average delivery rates of 25, 50, 75, and 100 μm/hour. With thesefigures and the results of the permeation studies, it is possible tocalculate the surface areas of the systems with ease. The results aresummarized in table 6.

TABLE 6 Calculated system surface areas of formulations A-F DeliveryCalculated area sizes (cm²) rate A B C D E F 25 μm/h 6.5 6.4 6.9 18.014.0 11.8 50 μm/h 13.0 12.8 13.8 36.0 28.0 23.6 75 μm/h 19.5 19.2 20.754.0 42.0 35.4 100 μm/h  26.0 25.6 27.6 72.0 56.0 47.2

The calculated surface areas all lie within an acceptable range. Thesize of the microreservoir systems with membrane can be made smallerstill through the use of thinner membranes or membranes with a higher VAcontent, although in that case the control of the delivery of activesubstance by the membrane will be less effective.

Microreservoir systems as provided by this invention therefore show verygood permeation rates, which without a control membrane lead to TTSwhich are small in terms of area and are pleasant to wear. At the sametime, there is absolutely no possibility of any risk to the patient fromexcessive active substance intake due to leakage.

In the case of microreservoir systems with membranes, the membranecontrol which limits the delivery of active substance results in patchsizes which are larger but still acceptable.

All in all, therefore, microreservoir systems for fentanyl and thefentanyl analog derivatives constitute a decisive step forward in termsof wear comfort and patient safety from the known prior art.

The preparation examples which follow describe the preparation ofmicroreservoir systems with and without membranes.

EXAMPLE 1 Microreservoir System with 1,3-butanediol as Liquid,Formulation A

1 g of fentanyl base is dissolved in 9 g of 1,3-butanediol, thickenedwith 3% hydroxypropylcellulose. To this solution there are added 54.8 gof a 73% strength solution of an amine-resistant silicone adhesive inn-heptane (BIO-PSA 4301, Dow Corning) and the active substance solutionis dispersed in the solution of the silicone adhesive by rapid stirring.The dispersion is then knife-coated onto an abhesively coated film, theprotective layer to be removed later prior to use (Scotchpak 1022, 3M),in a thickness which following removal of the n-heptane by drying at 30°C. for 15 minutes results in a coating weight of 135 g/m². The dry filmis then laminated with the active substance impermeable backing layer(Scotchpak 1220, 3M) and the finished transdermal therapeutic system ispunched from the overall laminate which results.

EXAMPLE 2 Microreservoir System with Dipropylene Glycol as Liquid,Formulation B

1 g of fentanyl base is dissolved in 4.6 g of dipropylene glycol,thickened with 2% hydroxypropylcellulose. To this solution there areadded 30.5 g of a 73% strength solution of an amine-resistant siliconeadhesive in n-heptane (BIO-PSA 4301, Dow Corning) and the activesubstance solution is dispersed in the solution of the silicone adhesiveby rapid stirring. The dispersion is then knife-coated onto anabhisively coated film, the protective layer to be removed later priorto use (Scotchpak 1022, 3M), in a thickness which following removal ofthe n-heptane by drying at 30° C. for 15 minutes results in a coatingweight of 85 g/m². The dry film is then laminated with the activesubstance impermeable backing layer (Scotchpak 1220, 3M) and thefinished transdermal therapeutic system is punched from the overalllaminate which results.

EXAMPLE 3 Microreservoir System with Transcutol as Liquid, Formulation C

1 g of fentanyl base is dissolved in 3 g of Transcutol, thickened with4% ethylcellulose. To this solution there are added 22 g of a 73%strength solution of an amine-resistant silicone adhesive in n-heptane(BIO-PSA 4301, Dow Corning), and the active substance solution isdispersed in the solution of the silicone adhesive by rapid stirring.The dispersion is then knife-coated onto an abhesively coated film, theprotective layer to be removed later prior to use (Scotchpak 1022, 3M),in a thickness which following removal of the n-heptane by drying at 30°C. for 15 minutes results in a coating weight of 65 g/m². The dry filmis then laminated with the active substance impermeable backing layer(Scotchpak 1220, 3M) and the finished transdermal therapeutic system ispunched from the overall laminate which results.

EXAMPLES 4-6 Microreservoir Systems with Membranes, Formulations D, E,and F

The solution of an amine-resistant silicone adhesive (BIO-PSA 4301, DowCorning) is knife-coated to an abhesively coated film (Scotchpak 1022,3M) in a thickness such that removal of the n-heptane by drying at 30°C. for 15 minutes gives a coating weight of 20 g/m². The dried film islaminated with a membrane (EVA, 50 μm, 9% VA, 3M).

The protective layer is removed from the laminates from examples 1-3 andthe laminate consisting of active substance layer and backing layer islaminated onto this membrane. The resulting overall laminate(formulations D, E and F) are then punched to give the finishedtransdermal therapeutic systems.

In the figures, the elements shown are as follows:

-   1=backing layer-   2=active substance layer with microreservoirs-   3=microreservoir-   4=control membrane-   5=skin contact layer-   6=removable protective layer

1. A transdermal therapeutic system (TTS) containing an active substancehaving increased security against overdose of the active substancecomprising an active substance impermeable backing layer, an activesubstance layer, the active substance being fentanyl and/or a fentanylanalog derivative and/or a salt of fentanyl and/or a salt of a fentanylanalog derivative, where said active substance layer comprises a polymeror a polymer mixture with microreservoirs dispersed therein, wherein theactive substance is dissolved in the microreservoirs and a membranelayer following the skin side comprised of an ethylene-vinyl acetatecopolymer or a polyethylene or polypropylene microporous film;optionally a subsequent adhesive layer and a protective layer, which isremoved before use.
 2. The TTS of claim 1, characterized in that thepolymer is a pressure sensitive adhesive polymer.
 3. The TTS of claim 1,characterized in that the polymer is an amine-resistant polysiloxane. 4.The TTS of claim 1, characterized in that the microreservoirs contain aliquid.
 5. The TTS of claim 1, wherein the microreservoirs have anaverage diameter of about 5 to 50 μm.
 6. The TTS of claim 1,characterized in that at least 50% by weight of the active substance inthe TTS is contained within the microreservoirs.
 7. The TTS of claim 1,characterized in that the liquid comprises dipropylene glycol,diethylene glycol monoethyl ether, diethylene glycol diethyl ether,diethylene glycol monomethyl ether, diethylene glycol dimethyl ether,1,3-butanediol, 2,2-dimethyl 4-hydroxymethyl-1,3-dioxolane,2-pyrrolidone or N-methylpyrrolidone or a combination thereof.
 8. TheTTS of claim 1, characterized in that the liquid comprises an additivewhich increases the viscosity,.
 9. The TTS of claim 1, characterized inthat the concentration of the active substance in the active substancelayer is below 5% by weight.
 10. The TTS of claim 1, characterized inthat the weight of the active substance layer per unit area is between30 and 300 g/m².
 11. The TTS of claim 1, characterized in that itcomprises a membrane and where appropriate, an adhesive layer.
 12. TheTTS of claim 11, wherein where the membrane layer does not possessadhesive properties, an adhesive layer is located between membrane layerand protective layer.
 13. The TTS of claim 12, characterized in that theethylene-vinyl acetate copolymer has a vinyl acetate content of 2-25%and a thickness of between 20 and 150 μm.
 14. The TTS of claim 1,characterized in that the active substance layer further comprises asubstance which enhances the rate of permeation through human skin. 15.The TTS of claim 14, characterized in that the substance belongs to thegroup consisting of fatty acids, fatty acid esters, fatty alcohols, andglycerol esters.
 16. The TTS of claim 8, wherein the additive whichincreases the viscosity is ethylcellulose or hydroxypropylcellulose. 17.The TTS of claim 9, characterized in that the concentration of theactive substance in the active substance layer is below 4% by weight.18. The TTS of claim 1, wherein the fraction of the microreservoirs inthe active substance layer is up to 40% by weight.
 19. The TTS of claim1, wherein the polymer or polymer mixture is selected from the groupconsisting of polyisobutylenes.
 20. The TTS of claim 11, wherein themembrane is 50 μm thick and is made of an ethylene-vinyl acetatecopolymer having a vinyl acetate content of 9 wt.-%.
 21. The TTS ofclaim 1, wherein the active substance being fentanyl or a salt offentanyl, at least 50% by weight of the active substance in the TTS iscontained within the microreservoirs, the liquid comprises dipropyleneglycol, diethylene glycol monoethyl ether, diethylene glycol diethylether, diethylene glycol monomethyl ether, diethylene glycol dimethylether, 1,3-butanediol, 2,2-dimethyl4-hydroxymethyl-1,3-dioxolane,2-pyrrolidone or N-methylpyrrolidone or a combination thereof, and theliquid comprises an additive which increases the viscosity.
 22. The TTSof claim 21, wherein the active substance is present completelydissolved in the microreservoirs and the additive which increases theviscosity is ethylcellulose or hydroxypropylcellulose.